Topical formulations having enhanced bioavailability

ABSTRACT

The present disclosure provides compositions suitable for delivering lipophilic bioactive agents. The compositions may be utilized to treat numerous diseases and conditions that would benefit from the application of a lipophilic bioactive agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 60/919,554, filed Mar. 22, 2007, the entiredisclosure of which is incorporated by reference herein.

BACKGROUND

Cancer is presently one of the leading causes of death in developednations. Although recent research has vastly increased our understandingof many of the molecular mechanisms of tumorigenesis and has providednumerous new avenues for the treatment of cancer, standard treatmentsfor most malignancies remain gross resection, chemotherapy, andradiotherapy. While increasingly successful, each of these treatmentsmay cause numerous undesired side effects. For example, surgery mayresult in pain, traumatic injury to healthy tissue, and scarring.Radiotherapy and chemotherapy may cause nausea, immune suppression,gastric ulceration and secondary tumorigenesis.

Improved methods for the treatment of diseases, including cancer, andcompositions capable of delivering bioactive agents to aid in thetreatment of diseases and other conditions remain desirable.

SUMMARY

The present disclosure provides compositions suitable for administeringlipophilic bioactive agents to a subject. The lipophilic bioactiveagents may be delivered by any route of administration. In embodiments,the lipophilic bioactive agent may be contained in liposomes.

Methods for forming compositions containing liposomes possessinglipophilic bioactive agents are also provided. In embodiments thelipophilic bioactive agent may be prepared as a first phase, optionallyin combination with a solubilizer, while a second phase may be preparedcontaining at least one phospholipid. The two phases may be combined,thereby forming liposomes possessing lipophilic bioactive agent.

In embodiments, liposomes possessing lipophilic bioactive agent may becombined with additional carriers for administration to a subject. Suchcarriers may include, in embodiments, oil phases, water phases,neutralizing or buffer phases, pigments, combinations thereof, and thelike.

Compositions of the present disclosure including liposomes possessinglipophilic bioactive agents may also include permeation enhancers toenhance delivery of the bioactive agent.

In embodiments, compositions of the present disclosure may include aliposomal concentrate including a phospholipid such as lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, and combinations thereof, at least onelipophilic bioactive agent, and at least one solubilizer. The liposomalconcentrate may be in combination with at least one pharmaceuticallyacceptable carrier possessing at least one permeation enhancer in anamount from about 0.5% by weight to about 20% by weight of thecomposition. The phospholipid may present in the composition in anamount from about 2% to about 20% by weight of the composition and thebioactive agent may be present in an amount from about 0.5% to about 20%by weight of the composition.

In other embodiments, a composition of the present disclosure mayinclude an oil phase, a water phase, a neutralization phase, a pigmentphase, and a liposomal concentrate. The oil phase may include C12-15alkyl benzoates, cetyl alcohol, stearyl alcohol, glyceryl stearate, andpolyethylene glycol 100 stearate, and may be present in an amount offrom about 5% to about 20% by weight of the composition. The water phasemay include glycerin, propylene glycol, ethoxydiglycol, phenoxyethanol,water, and a crosslinked acrylic acid polymer dispersion includingphenoxyethanol, propylene glycol, water, and a crosslinked acrylic acidpolymer, and may be present in an amount of from about 60 to about 80%by weight of the composition. The neutralization phase may includewater, triethanolamine, sodium lactate, and lactic acid, and may bepresent in an amount of from about 0.1% to about 15% by weight of thecomposition. The pigment may include titanium dioxide present in anamount of from about 0.2% to about 2% by weight of the composition. Theliposomal concentrate may include a polyethoxylated fatty acid ester ofsorbitan, coenzyme Q10, a phosphatidylcholine lecithin, phenoxyethanol,propylene glycol, and water, and may be present in an amount of fromabout 0.1% to about 30% by weight of the composition. In embodiments,the propylene glycol and ethoxydiglycol from the water phase may act aspermeation enhancers and may be present in a combined amount of from 3%by weight to about 15% by weight of the composition, and the coenzymeQ10 may be present in an amount of from about 0.75% by weight to about10% by weight of the composition.

Any disease or condition that would benefit from the administration of alipophilic bioactive agent may be treated with liposomes possessinglipophilic bioactive agents as described herein, including compositionscontaining such liposomes possessing lipophilic bioactive agentsoptionally in combination with a permeation enhancer.

BRIEF DESCRIPTION OF THE FIGURES

Various embodiments of the present disclosure will be described hereinbelow with reference to the Figures wherein:

FIG. 1 is a graph depicting the epidermal CoQ10 concentration in a malepig after treatment with a composition of the present disclosure havinga permeation enhancer; and

FIG. 2 is a graph depicting the epidermal CoQ10 concentration in afemale pig after treatment with a control composition.

DETAILED DESCRIPTION

In accordance with the present disclosure, a formulation is provided forimproved administration of lipophilic bioactive agents, which may alsobe referred to herein as hydrophobic bioactive agents. As used herein, alipophilic bioactive agent includes an agent that is insoluble in water.Specifically, lipophilic bioactive agents, as used herein, will have asolubility in water that is less than about 1 part of bioactive drug inabout 1000 parts of water.

In embodiments the lipophilic bioactive agents may be placed inliposomes and administered to a patient. In accordance with the presentdisclosure, any phospholipid and/or phospholipid derivative such as alysophospholipid may be utilized to form a liposome for encapsulatingthe lipophilic bioactive agent. Suitable phospholipids and/orphospholipid derivatives include, but are not limited to, lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, combinations thereof, and the like.

In some embodiments, a lecithin derived from egg or soybean may beutilized as the phospholipid. Such lecithins include those commerciallyavailable as PHOSPHOLIPON® 85G, PHOSPHOLIPON® 90G, and PHOSPHOLIPON® 90H(the fully hydrogenated version of PHOSPHOLIPON® 90G) from AmericanLecithin Company, Oxford, Conn. Other suitable lecithins include LECINOLS-10 lecithin from Nikko Chemicals.

The above phospholipids or derivatives thereof may be utilized to formliposomes containing the bioactive agent. In embodiments, a lecithinhaving a high phosphatidylcholine content may be utilized to form aliposome. In some embodiments a high phosphatidylcholine lecithin whichmay be utilized includes PHOSPHOLIPON® 85G, a soy-derived lecithincontaining a minimum of about 85% of a linoleic acidbased-phosphatidylcholine. This lecithin is easy to use and is able toproduce submicron liposomes at low process temperatures (from about 20°C. to about 55° C.) without the addition of any other special additives.PHOSPHOLIPON® 85G contains, in addition to phosphatidylcholine,approximately 5-7% phosphatidic acid. The phosphatidic acid confers anegative surface charge to the resulting liposome vesicles, reducesprocessing time and process energy, and aids in the formation of stableliposomes.

Suitable lipophilic bioactive agents which may be enclosed in liposomesherein include, but are not limited to, analgesics, anti-inflammatoryagents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents,anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensiveagents, anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, erectile dysfunction improvement agents,immunosuppressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, cox-2inhibitors, leucotriene inhibitors, macrolides, muscle relaxants,nutritional agents, opioid analgesics, protease inhibitors, sexhormones, stimulants, muscle relaxants, anti-osteoporosis agents,anti-obesity agents, cognition enhancers, anti-urinary incontinenceagents, nutritional oils, anti-benign prostate hypertrophy agents,essential fatty acids, non-essential fatty acids, external analgesics(for example aspirin, nonsteroidal antiinflammatories and the like),steroidal antiinflammatory drugs (such as hydrocortisone and the like),skin bleaching agents (such as hydroquinone, kojic acid, sodiummetabisulfite, and the like), skin protectants, and combinationsthereof.

Specific, non-limiting examples of suitable lipophilic bioactive agentsinclude, but are not limited to, acutretin, albendazole, albuterol,aminogluthemide, amiodarone, amlodipine, amphetamine, amphotericin B,atorvastatin, atovaquone, azithromycin, baclofen, beclomethsone,benezepril, benzonatate, benzoquinones, betamethasone, bicalutanide,budesonide, bupropion, busulphan, butenafine, calcifediol,calciprotiene, calcitriol, camptothecan, candesartan, capsaicin,carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine,chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine,ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene,clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine,cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac,dicoumarol, digoxin, dihydro epiandrosterone, dihydroergotamine,dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan,ergocalciferol, ergotamine, essential fatty acid sources, etodolac,etoposide, famotidine, farnesol, fenofibrate, fentanyl, fexofenadine,finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion,frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide,glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen,irbesartan, irinotecan, isoprenoids, isosorbide dinitrate, isotreinoin,itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine,lanosprazole, leflunomide, lisinopril, loperamide, loratadine,lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone,mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen,metronidazole, metronidazole, miconazole, midazolam, miglitol,minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine,naratiptan, nelfinavir, nifedipine, nilsolidipine, nilutanide,nitrofurantoin, nizatidine, omeprazole, oprevelkin, osteradiol,oxaprozin, paclitaxel, paricalcitol, paroxetine, pentazocine,pioglitazone, pizofetin, pravastatin, prednisolone, probucol,progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene,refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir,rizatriptan, rosigiltazone, saquinavir, sertraline, sibutramine,sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan,tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene,telmisartan, teniposide, terbinafine, terzosin, tetrahydrocannabinol,tiagabine, ticlidopine, tirofibran, tizanidine, topiramate, topotecan,toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, valsartan,venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E,vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, andcombinations thereof. Salts, isomers and/or other derivatives of theabove-listed lipophilic bioactive agents may also be used, as well ascombinations thereof.

In embodiments, coenzyme Q10 may be utilized as the lipophilic bioactiveagent in accordance with the present disclosure. For example, coenzymeQ10 may be applied as described in International Publication No. WO2005/069916, the entire disclosure of which is incorporated by referenceherein. Coenzyme Q10, sometimes referred to herein as CoQ10, ubiquinone,or ubidecarenone, is a popular nutritional supplement and can be foundin capsule form in nutritional stores, health food stores, pharmacies,and the like, as a vitamin-like supplement to help protect the immunesystem through the antioxidant properties of ubiquinol, the reduced formof CoQ10. CoQ10 is found throughout most tissues of the human body andthe tissues of other mammals and is concentrated in the mitochondria.CoQ10 is very lipophilic and, for the most part, insoluble in water.

Other related compounds which may be administered instead of, or incombination with, CoQ10 include, but are not limited to, benzoquinones,isoprenoids, farnesols, farnesyl acetate, farnesyl pyrophosphate,1-phenylalanine, d-phenylalanine, dl-phenylalanine, 1-tyrosine,d-tyrosine, dl-tyrosine, 4-hydroxy-phenylpyruvate,4-hydroxy-phenyllactate, 4-hydroxy-cinnamate, dipeptides and tripeptidesof tyrosine or phenylalanine, 3,4-dihydroxymandelate,3-methoxy-4-hydroxyphenylglycol, 3-methoxy-4-hydroxymandelate, vanillicacid, phenylacetate, pyridoxine, S-adenosyl methionine, panthenol,mevalonic acid, isopentyl pyrophosphate,phenylbutyrate,4-hydroxy-benzoate,decaprenyl pyrophosphate, beta-hydroxybutyrate,3-hydroxy-3-methyl-glutarate, acetylcarnitine, acetoacetylcarnitine,acetylglycine, acetoacetylglycine, carnitine, acetic acid, pyruvic acid,3-hydroxy-3-methylglutarylcarnitine, all isomeric forms of serine,alanine, cysteine, glycine, threonine, hydroxyproline, lysine,isoleucine, and leucine, even carbon number C4 to C18 fatty acids(butyric, caproic, caprylic, capric, lauric, myristic, palmitic, andstearic acids) salts of carnitine and glycine, e.g., palmitoylcarnitineand palmitoylglycine, and 4-hydroxy-benzoate polyprenyltransferase, anysalts of these compounds, as well as any combinations thereof, and thelike.

In embodiments, it may be desirable to form a stable, skin penetratingbioactive agent/liposomal concentrate for delivery of the lipophilicbioactive agent. Thus, in forming a liposome, it may be desirable tocombine the lipophilic bioactive agent with a material that cansolubilize the lipophilic bioactive agent in a suitable media, in someembodiments water, for subsequent encapsulation in a liposome. Suitablematerials which may be utilized as a solubilizer for the lipophilicbioactive agent include, for example, polyoxyalkylene dextrans, fattyacid esters of saccharose, fatty alcohol ethers of oligoglucosides(e.g., akylpolyglucosides, including those commercially available asTRITON™ from Dow Chemical North America, Midland, Mich., USA), fattyacid esters of glycerol (e.g., glycerol mono/distearate or glycerolmonolaurate), and polyoxyethylene type compounds (e.g., polyoxyethylene,polyethylene glycol, polyethylene oxide, and copolymers thereof,including those commercially available as SOLUTOL™ CREOMOPHOR™,MACROGOL™, CARBOWAX™, and POLYOXYL™).

Suitable solubilizers also include polyethoxylated fatty acid esters ofsorbitan (e.g., polysorbates, including those commercially available asTWEEN™ and SPAN™) fatty acid esters of poly(ethylene oxide) (e.g.,polyoxyethylene stearates), fatty alcohol ethers of poly(ethylene oxide)(e.g., polyoxyethylated lauryl ether), alkylphenol ethers ofpoly(ethylene oxide) (e.g., polyethoxylated octylphenol),polyoxyethylene-polyoxypropylene block copolymers (also known aspoloxamers, including those commercially available as “PLURONICS”), andethoxylated fats and oils (e.g., ethoxylated castor oil, orpolyoxyethylated castor oil, also known as polyethylene glycol-glyceryltriricinoleate). Combinations of these solubilizers may also be utilizedin embodiments. Such combinations are available from standard commercialsources.

In some embodiments, suitable solubilizers include polysorbates, e.g.those sold under the name TWEEN™. Examples of such polysorbates includepolysorbate 80 (TWEEN™ 80), polysorbate 20 (TWEEN™ 20), polysorbate 60(TWEEN™ 60), polysorbate 65 (TWEEN™ 65), polysorbate 85 (TWEEN™ 85), andthe like, and combinations including these materials with other similarsurfactants, including ARLACEL® surfactants commercially available fromICI Americas, as long as the HLB (Hydrophile-Lipophile Balance) of thesurfactant and surfactant mixture favors the formation of an O/W typeemulsion system.

To assist in solubilization, it may be desirable, in embodiments, toheat the lipophilic bioactive agent and solubilizer for a suitableperiod of time. The temperature of heating and time of heating maydepend upon the specific lipophilic bioactive agent, the intrinsicthermal stability of the bioactive agent, and the specific solubilizerto be utilized. For example, in embodiments the lipophilic bioactiveagent and solubilizer may be heated to a temperature from about 40° C.to about 65° C., in embodiments from about 50° C. to about 55° C., for aperiod of time from about 5 minutes to about 60 minutes, in embodimentsfrom about 15 minutes to about 30 minutes. The heating time andsolubilization of the lipophilic active agent may be reduced if thelipophilic active and solubilizer mixture is agitated. The weight ratioof lipophilic bioactive agent to solubilizer may be about 1:1, inembodiments from about 1:1 to about 4:2, in other embodiments from about1:2 to about 3:2.

In embodiments, a solubilizer such as polysorbate 80 may be capable ofdissolving lipophilic bioactive agent, in embodiments CoQ10, at highlevels, with the lipophilic bioactive agent completely soluble in thesolubilizer at a ratio of from about 1:2 to about 3:2, when heated tofrom about 50° C. to about 55° C., a temperature which exceeds themelting point of CoQ10 (which is from about 47° C. to about 48° C.).

The amount of solubilizer added to the lipophilic bioactive agent willdepend upon the solubilizer, the lipophilic bioactive agent, and thephospholipids utilized to form the liposomes. In embodiments, acomposition of the present disclosure possessing liposomes including alipophilic bioactive agent therein may possess a solubilizer in anamount from about 0.2% to about 12% by weight, in embodiments from about1.5% to about 6.5% by weight.

The solution of lipophilic bioactive agent and solubilizer, sometimesreferred to herein as a first phase, may then be combined with thephospholipid as described above, in some embodiments lecithin. Inembodiments, it may be desirable to place the phospholipid in adispersion, sometimes referred to herein as a second phase, to which thesolution of lipophilic bioactive agent and solubilizer (i.e., the firstphase) are added. Suitable solvents for forming a dispersion/secondphase including the phospholipid include, but are not limited to, water,purified water, deionized water, ethanol, isopropanol, glycols,diglycols, polyglycols, combinations thereof, and the like. Where added,the solvent may be present in an amount from about 70% by weight toabout 98% by weight of the second dispersion, in embodiments from about78% by weight to about 93% by weight of the second dispersion, with thephospholipid being present in an amount from about 2% by weight to about30% by weight of the second dispersion, in embodiments from about 7% byweight to about 22% by weight of the second dispersion.

In embodiments, the phospholipid may be present in an amount of fromabout 1% by weight to about 20% by weight of the combination ofphospholipid, solubilizer, and lipophilic bioactive agent, inembodiments from about 4% by weight to about 12% by weight of thecombination of phospholipid, solubilizer, and lipophilic bioactiveagent.

In embodiments, solubilization of a lipophilic bioactive agent such asCoQ10 in a material that has both lipophilic and hydrophilic properties,in embodiments a polysorbate such as polysorbate 80, may assist inliposome formulation by forming water-dispersible CoQ10 forencapsulation by a high phosphatidylcholine lecithin, such asPHOSPHOLIPON® 85G.

In some embodiments, additional components may be combined with thissecond phase to enhance formulation of the liposomes possessing alipophilic bioactive agent, to improve overall rheological andprocessing properties, and to insure microbiological integrity of theresulting liposomal concentrate during storage. Such components include,without limitation, absorbents, antifoaming agents, acidifiers,alkalizers, buffers, antimicrobial agents, antioxidants (for exampletocopherols, BHT, polyphenols, phytic acid) binders, biologicaladditives, chelating agents (for example, disodium EDTA, tetrasodiumEDTA, sodium metasilicate, and the like), denaturants, preservatives(for example imidazolidinyl urea, diazolidinyl urea, phenoxyethanol,methylparaben, ethylparaben, propylparaben, and the like), reducingagents, solubilizing agents, solvents, viscosity modifiers, humectants,thickening agents, and combinations thereof. These additional componentsmay be present in an amount from about 0.001% by weight to about 10% byweight of the second phase, in embodiments from about 0.1% by weight toabout 1% by weight of the second phase.

Examples of suitable humectants which may be added to the second phaseinclude, but are not limited to, polyols and polyol derivatives,including glycerol, diglycerol, triglycerol, ethylene glycol, propyleneglycol, butylene glycol, pentylene glycol (sometimes referred to hereinas 1,2-pentane diol), isopreneglycol (1,4-pentane diol), 1,5-pentanediol, hexylene glycol, erythritol, 1,2,6-hexanetriol, polyethyleneglycols such as PEG-4, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-12,PEG-14, PEG-16, PEG-18, PEG-20, combinations thereof, sugars and sugarderivatives (including fructose, glucose, maltose, maltitol, mannitol,inositol, sorbitol, sorbityl silanediol, sucrose, trehalose, xylose,xylitol, glucuronic acid and salts thereof), ethoxylated sorbitol(Sorbeth-6, Sorbeth-20, Sorbeth-30, Sorbeth-40), and combinationsthereof. In some embodiments, a commercially available 1,2-pentane diolsuch as HYDROLITE-5® pentylene glycol (commercially available fromSymrise GmbH) may be utilized. In other embodiments, a propylene glycolmay be utilized. Where utilized, such humectants may be present inamounts from about 0.1% by weight to about 20% by weight of the secondphase, in embodiments from about 3% by weight to about 10% by weight ofthe second phase.

In some embodiments, a preservative such as phenoxyethanol and ahumectant such as butylene glycol, hexylene glycol, pentylene glycoland/or propylene glycol may both be added to the second phase. Inembodiments, the pentylene glycold and/or propylene glycol may providehumectancy and assist in the preservation of the concentrate whencombined with phenoxyethanol. The phenoxyethanol and pentylene glycoland/or propylene glycol mix should be water soluble and non-volatile.This is in contrast with the use of ethanol for preservation, which isoften utilized by suppliers of liposomal dispersions. Where present,such preservatives may be present in amounts from about 0.01% by weightto about 3% by weight of the second phase, in embodiments from about0.3% by weight to about 1% by weight of the second phase.

The dispersion containing the phospholipid, sometimes referred to hereinas the second phase, and the solution containing the lipophilicbioactive agent and solubilizer, sometimes referred to herein as thefirst phase, may be homogenized by mixing at high shear to form aliposomal concentrate utilizing homogenizers, mixers, blenders andsimilar apparatus within the purview of those skilled in the art. Insome embodiments, commercially available homogenizers including aSilverson L4RT Homogenizer or similar types of stator/rotor homogenizersmade by Gifford-Wood, Frain, IKA and others, as well as multi-stagehomogenizers, colloid mills, sonolators, or other types of homogenizers,may be used to produce submicron liposomal dispersions of the lipophilicbioactive agent. The stator/rotor type homogenizers described above havean operational range of from about 100 rpm to about 12,000 rpm, and maybe supplied with a range of low shear, standard shear, and/or high shearhead screens.

Homogenization may occur by mixing the two phases at suitable speeds of,for example, from about 4,000 rpm to about 12,000 rpm, in embodimentsfrom about 5,000 rpm to about 10,000 rpm, in some embodiments about7,000 rpm. The shear rate of the homogenizer may also be increased ordecreased independent of the speed of the homogenizing shaft byincreasing or decreasing the size of the processing screen surroundingthe homogenizer head. In embodiments, liposomes may be made with both astandard emulsification screen and a high shear screen, for example,those screens supplied with the Silverson L4RT homogenizer. Mixing mayoccur for a suitable period of time of less than about 90 minutes, inembodiments from about 2 minutes to about 60 minutes, in embodimentsfrom about 5 minutes to about 45 minutes. The resulting liposomes mayhave a particle size of less than about 600 nm, in embodiments fromabout 100 nm to about 500 nm, in other embodiments from about 200 nm toabout 400 nm, in some embodiments about 300 nm.

In embodiments, the two phases may be separately heated to a temperatureof from about 45° C. to about 65° C., in some embodiments from about 50°C. to about 55° C., and mixed with high shear homogenization at speedsand for periods of time described above to form submicron liposomes ofCoQ10. Where the lipophilic bioactive agent is CoQ10, the processingtemperature for the CoQ10 phase, the water/phospholipid phase, and thecombined phases should not exceed about 55° C. in order to avoidoxidative degradation of the CoQ10. Processing the mixture at atemperature of from about 45° C. to about 55° C. may be useful to obtaina desired viscosity of the concentrate from about 5,000 cP to about100,000 cP, in embodiments from about 15,000 cP to about 40,000 cP at atemperature of from about 35° C. to about 45° C. In some embodiments,processing for extended periods, e.g., for up to about 60 minutes at thespeeds noted above within this temperature range, should not adverselyimpact the integrity of the resulting liposomes.

The bioactive agent may be present in the resulting concentrate in anamount of from about 10% by weight of the concentrate to about 30% byweight of the concentrate, in embodiments from about 18% by weight ofthe concentrate to about 26% by weight of the concentrate, in someembodiments from about 21% by weight of the concentrate to about 22% byweight of the concentrate. The amount of phospholipids in theconcentrate may be from about 1% by weight of the concentrate to about20% by weight of the concentrate, in embodiments from about 4% by weightof the concentrate to about 12% by weight of the concentrate, with thebalance being the solubilizer, solvent, humectant and preservative.

In embodiments, it may be desirable to include a permeation enhancer inany composition including the liposomes described above. The permeationenhancer may increase the bioavailability of the resulting liposomescontaining the lipophilic bioactive agent. While liposomes of thepresent disclosure may be administered by any route within the purviewof those skilled in the art, the addition of a permeation enhancer maybe especially beneficial for topical routes of administration.

Suitable permeation enhancers include, but are not limited to,ethoxydiglycol (also known as diethylene glycol monoethyl ether,commercially available as TRANSCUTOL and TRANSCUTOL P from Gattefosseand TRIVALIN CG from Tri-K Industries), 1,3-butylene glycol, isopentyldiol, 1,2-pentane diol, propylene glycol, 2-methyl propan-2-ol,propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol,di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, polyoxyethylene(2)methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid,propan-1-ol, 1,4 dioxane, tetrahydrofuran, butan-1,4-diol, propyleneglycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol,polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol,dioctyl adipate, dicapryl adipate, diisopropyl adipate, diisopropylsebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctylsebacate, dibuyl suberate, dioctyl azelate, dibenzyl sebacate, dibutylphthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butylmyristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethylcaproate, ethyl salicylate, isopropyl palmitate, ethyl laurate,2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzylbenzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate,butyl stearate, benzyl salicylate, 2-hyroxyoctanoic acid, dimethylsulphoxide, methyl sufonyl methane (MSM), n,n-dimethyl acetamide,n,n-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone,5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone,1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters,tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,1-dodecylazacyloheptan-2-one, combinations thereof, and the like.

The amount of permeation enhancer in the compositions of the presentdisclosure, including any combination of any and all phases describedherein, may be less than about 25% by weight of the composition, inembodiments from about 0.5% by weight to about 20% by weight of thecomposition, in other embodiments from about 3% by weight to about 15%by weight of the composition, in yet other embodiments from about 5% byweight of the composition to about 10% by weight of the composition.

In embodiments, a suitable permeation enhancer may includeethoxydiglycol. In other embodiments, a suitable permeation enhancer mayinclude ethoxydiglycol in combination with another permeation enhancersuch as propylene glycol, pentylene glycol, or any other permeationenhancer described above.

Surprisingly, and as detailed below in the Examples, it has beendiscovered that, in some embodiments, lower amounts of ethoxydiglycol,rather than higher amounts of ethoxydiglycol, optionally in combinationwith other permeation enhancers, may provide enhanced bioavailability ofa lipophilic bioactive agent, in embodiments CoQ10, when administeredtopically. In embodiments, suitable amounts of ethoxydiglycol may befrom about 0.5% to about 10% by weight of the composition, inembodiments from about 2% to about 8% by weight of the composition, inembodiments from about 4% to about 6% by weight of the composition.

Once formed, the resulting liposomes, which may be in a concentrate, maybe administered to a patient or, in embodiments, may be combined withany pharmaceutically acceptable carrier. As used herein the terms“pharmaceutically acceptable carrier” and “pharmaceutically acceptablecarriers” refers to those compounds which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of asubject without undue toxicity, irritation, allergic response, and thelike, commensurate with a reasonable benefit/risk ratio, and effectivefor their intended use, as well as salts and biocompatible derivativesof those compounds. As used herein, a pharmaceutically acceptablecarrier includes any and all solvents, including water, dispersionmedia, coatings, antibacterial and antifungal agents, stabilizingexcipients, absorption enhancing or delaying agents, polymers, includingpolymeric binders and polymeric adhesives, combinations thereof, and thelike. Such materials should be non-toxic to the recipients at thedosages and concentrations employed, and may include buffers such asTRIS HCl, phosphate, citrate, acetate and other organic acid salts;antioxidants such as ascorbic acid; low molecular weight (less thanabout ten residues) peptides such as polyarginine, proteins such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidinone; amino acids such as glycine, glutamic acid,aspartic acid, or arginine; monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannose,or dextrins; chelating agents such as EDTA; sugar alcohols such asmannitol or sorbitol; counterions such as sodium and/or nonionicsurfactants such as TWEEN, PLURONICS and/or polyethylene glycol.

The use of such media and agents for pharmaceutically active substancesis within the purview of those skilled in the art. Supplementary activeingredients can also be incorporated into the compositions.

In embodiments, the above carriers may be utilized alone or incombination to form a carrier system. Suitable pharmaceuticallyacceptable carrier systems are within the purview of those skilled inthe art and may include, but are not limited to, lotions, creams, gels,emulsions, dispersions, solids, solid sticks, semi-solids, aerosol ornon-aerosol foams, sprays, serums, transdermal adhesive patch systems,combinations thereof, and the like. In embodiments, the liposomes may bein a liposomal concentrate and may be introduced to a patient with apermeation enhancer as described above. In embodiments, the permeationenhancer may be present in a water phase added to the liposomalconcentrate to form a composition of the present disclosure. Inembodiments, the formulation may be used for transdermal delivery.

Lotions or creams including the liposomes described above may includeadditional phases for formation of the lotion and/or cream. For example,in some embodiments, a composition of the present disclosure may includea lotion formed by combining the liposomes described above andpermeation enhancer with additional oil phases, water phases,neutralizing phases, pigments, combinations thereof, and the like. Inembodiments, these combined phases may form the pharmaceuticallyacceptable carrier described above.

As also noted above, in embodiments the permeation enhancer may be inone of the additional phases, for example, the water phase.

Similarly, the concentrate described above may be placed in any suitablesolvent, including water, for administration, or combined with apolymeric binder and/or adhesive for administration as a solid,semi-solid, and the like. Emulsions and/or dispersions may be formed bycombining the liposomal concentrate with surfactants utilizing any meanswithin the purview of those skilled in the art.

Where additional phases are present in the formation of a composition ofthe present disclosure in the form of a lotion or cream, the liposomeconcentrate or dispersion may be present in an amount of from about 0.1%to about 30% by weight of the lotion or cream, in embodiments from about5 to about 25% by weight of the lotion or cream.

The bioactive agent may thus be present in the final composition, inembodiments a lotion, cream or any other suitable form described above,in amounts of from about 0.5% by weight to about 20% by weight of thecomposition, in embodiments from about 0.75% by weight to about 10% byweight of the composition, in other embodiments from about 1% by weightto about 7.5% by weight of the composition, in other embodiments fromabout 1.25% by weight to about 5% by weight of the composition, in otherembodiments from about 1.5% by weight to about 3% by weight of thecomposition.

For example, in some embodiments a lotion or cream including theliposome concentrate described above may include an oil phase which, inturn, may include emollients, fatty alcohols, emulsifiers, combinationsthereof, and the like. For example, an oil phase could includeemollients such as C12-15 alkyl benzoates (commercially available asFINSOLV™ TN from Finetex Inc. (Edison, N.J.)), capric-caprylictriglycerides (commercially available from Huls as MIGLYOL™ 812), andthe like. Other suitable emollients which may be utilized includevegetable derived oils (corn oil, safflower oil, olive oil, macadamiannut oil, etc.); various synthetic esters, including caprates,linoleates, dilinoleates, isostearates, fumarates, sebacates, lactates,citrates, stearates, palmitates, and the like; synthetic medium chaintriglycerides, silicone oils or polymers; fatty alcohols such as cetylalcohol, stearyl alcohol, cetearyl alcohol, lauryl alcohol, combinationsthereof, and the like; and emulsifiers including glyceryl stearate,PEG-100 stearate, Glyceryl Stearate, Glyceryl Stearate SE, neutralizedor partially neutralized fatty acids, including stearic, palmitic,oleic, and the like; vegetable oil extracts containing fatty acids,Ceteareth-20,Ceteth-20, PEG-150 Stearate, PEG-8 Laurate, PEG-8 Oleate,PEG-8 Stearate, PEG-20 Stearate, PEG-40 Stearate, PEG-150 Distearate,PEG-8 Distearate, combinations thereof, and the like; or other non-polarcosmetic or pharmaceutically acceptable materials used for skinemolliency within the purview of those skilled in the art, combinationsthereof, and the like.

The emollients, in embodiments C12-15 alkyl benzoates, may be includedfor emolliency and spreadability. Where present, the emollient may bepresent in an amount from about 0.2% by weight to about 15% by weight ofthe total composition, in embodiments from about 2% by weight to about6% by weight of the total composition. Alcohols such as cetyl alcoholand stearyl alcohol may be added to impart body or texture to a cream.Where both cetyl alcohol stearyl alcohol are utilized, the ratio ofcetyl alcohol to stearyl alcohol may be from about 2:1 to about 1:2,with the waxy alcohols making up from about 1 to about 6 weight percentof the total composition, in embodiments from about 2% by weight toabout 4% by weight of the total composition.

As noted above, this oil phase may also include emulsifiers. Suitableemulsifiers include, but are not limited to, stearates includingglyceryl stearate, PEG-100 stearate, glyceryl stearate SE, glycerylstearate citrate, combinations thereof, and the like. In embodiments, acombination of stearates may be utilized in the oil phase as anemulsifier. For example, a glyceryl stearate and PEG-100 stearatemixture (in embodiments, a mixture of glyceryl stearate and polyethyleneglycol 100 stearate commercially available as ARLACEL® 165 from ICIAmericas) may be used as an emulsifier to form an oil-in-water (o/w)emulsion. In such a combination, the PEG-100 stearate may act as theprimary emulsifier and the glyceryl stearate may be a co-emulsifier. Theemulsifier may be present in an amount from about 2% by weight to about8% by weight of the total composition, in embodiments from about 3% byweight to about 5% by weight of the total composition.

The weight ratio of emulsifier to emollients as described above in thisoil phase may be from about 10:1 to about 1:2, in some embodiments fromabout 2:1 to about 1:1.

Where present, an oil phase may be present in an amount of from about 5%to about 20% by weight of a lotion or cream, in embodiments from about8% to about 15% by weight of a lotion or cream. Lotions or creams formedwith the above liposomes may also include a water phase, which may, inembodiments, include the permeation enhancer described above as well asthose items combined to form the second phase described above, includinghumectants and preservatives. Thus, in embodiments, the water phaseutilized in formation of a lotion or cream possessing liposomes asdescribed herein may include the second phase described above. Inaddition, in embodiments it may be desirable to add a viscositymodifier, sometimes referred to herein as a viscosity agent, to providethe lotion and/or cream with a desired viscosity.

Suitable viscosity agents which may be added to the water phase includewater soluble polymers, including anionic polymers and nonionicpolymers. Useful polymers include vinyl polymers such as cross linkedacrylic acid polymers with the CTFA name CARBOMER, pullulan, mannan,scleroglucans, polyvinylpyrrolidone, polyvinyl alcohol, guar gum,hydroxypropyl guar gum, xanthan gum, acacia gum, arabia gum, tragacanth,galactan, carob gum, karaya gum, locust bean gum, carrageenin, pectin,amylopectin, agar, quince seed (Cydonia oblonga Mill), starch (rice,corn, potato, wheat), algae colloids (algae extract), microbiologicalpolymers such as dextran, succinoglucan, starch-based polymers such ascarboxymethyl starch, methylhydroxypropyl starch, alginic acid-basedpolymers such as sodium alginate, alginic acid propylene glycol esters,acrylate polymers such as sodium polyacrylate, polyethylacrylate,polyacrylamide, polyethyleneimine, and inorganic water soluble materialssuch as bentonite, aluminum magnesium silicate, laponite, hectonite, andanhydrous silicic acid. Combinations of the foregoing may also be usedin embodiments. In some embodiments, a CARBOMER such as CARBOMER 940 maybe added as a viscosity agent to control the rheological properties ofthe cream formulas and add stability to the primary emulsion.

Where utilized, a viscosity agent may be present in an amount from about0.1% to about 2% by weight of the composition, in embodiments from about0.25% to about 0.6% of the composition.

Alternatively, the water phase may contain other soluble humectants suchas glycols, polyols, lactate salts, amino acids, peptides, sugars, urea,sodium PCA, hyaluronic acid, or salts thereof, or any other suitablehumectant or water soluble or water-dispersible moisturizer within thepurview of those skilled in the art. The weight ratio of humectants topermeation enhancer to preservative to viscosity agent may be from about20:10:1:1 to about 10:20:1:1, in some embodiments from about 15:10:2:1to about 10:15:1:1.

Thus, as noted above, the water phase utilized to form a lotion and/orcream of the present disclosure may include water, humectants,preservatives, viscosity agents, and permeation enhancers. For example,in embodiments a suitable water phase may include a combination ofglycerine, pentylene glycol and/or propylene glycol, ethoxydiglycol,phenoxyethanol, water, and CARBOMER 940. Such a water phase may containglycerine for skin moisturization and humectancy; propylene glycol forhumectancy and to aid in skin penetration and to improve themicrobiological preservation profile; ethoxydiglycol to enhance CoQ10skin penetration of the liposomes; phenoxyethanol for microbiologicalpreservation; purified water as the phase solvent, and CARBOMER 940 tocontrol the rheological properties of the cream formulas and to addstability to the primary emulsion.

In some embodiments, the viscosity agent may be added to the water phaseas a dispersion in a humectant as described above, optionally incombination with water, optionally in combination with a preservative asdescribed above. For example, in embodiments CARBOMER 940 may be addedas a dispersion such as a 2% dispersion containing CARBOMER 940dispersed in a mixture of water, propylene glycol, and phenoxyethanol.This CARBOMER 940 dispersion may be made separately in a batchmanufacturing process. Where a viscosity agent such as CARBOMER 940 isadded as a separate dispersion to the water phase, the weight ratio ofviscosity agent to humectant to preservative to water may be from about0.3:2:0.05:10 to about 0.5:1:0.2:10, in some embodiments from about0.1:0.5:0.05:9 to about 0.2:1:0.1:9.

Where present, a water phase may be present in an amount of from about60% to about 80% by weight of a lotion or cream, in embodiments fromabout 63% to about 71% by weight of a lotion or cream.

In some embodiments, a third phase, which may be referred to herein as aneutralization phase or buffer phase, may also be added in the formationof a cream or lotion. The components of such a phase may include, butare not limited to, water, amines including triethanolamine,triisopropanolamine, 2-amino-2methyl-1,3-propanediol,tris(hydroxymethyl)amine, 2-aminobutanol, sodium hydroxide, potassiumhydroxide, salts such as sodium lactate, potassium lactate, sodiumcitrate, potassium citrate, sodium or potassium mono-, di, ortri-phosphate, sodium borate, potassium borate, acids such as lacticacid, citric acid, phosphoric acid, boric acid, combinations thereof,and the like. The water may act as a solvent and a diluent for the otheringredients in this phase. The amine such as triethanolamine may act asa neutralizer of an acid component in the water phase, such as theCARBOMER acrylic acid copolymer; additional salts such as a sodiumlactate solution (60% w/w in water) and additional acids such as lacticacid may be added as a buffer system to adjust and maintain the final pHof the cream at from about 4.8 to about 6, in some embodiments fromabout 5 to about 5.5 (within the natural pH range of the skin). Inembodiments, a pH of about 5 or higher may be useful, as the CARBOMER940 acrylic copolymer of the water phase or similar material should befully neutralized and develop its full viscosity potential.

In embodiments a suitable amount of amine such as triethanolamine may beadded so that it is present in an amount from about 0.5% to about 2% byweight of the final composition, in embodiments from about 1% to about1.5% by weight of the final composition. A suitable amount of salt suchas sodium lactate may be added so that it is present in an amount fromabout 0.5% to about 3% by weight of the final composition, inembodiments from about 1% to about 1.5% by weight of the finalcomposition. In embodiments, a suitable amount of acid such as lacticacid may be added so that it is present in an amount from about 0% to 1%by weight of the final composition, in some embodiments about 0.25% toabout 0.75% by weight of the final composition, in some embodimentsabout 0.5% by weight of the final composition. The neutralizer and/orbuffer may be added so that it is present in an amount from about 0.01%to about 10% by weight of the final composition, in embodiments fromabout 2% to about 4% by weight of the final composition.

Where present, the neutralizing phase may be present in an amount offrom about 0.1% to about 15% by weight of a lotion or cream, inembodiments from about 5% to about 8% by weight of a lotion or cream.

In embodiments, where the lipophilic bioactive agent is CoQ10, a creamwithout a pigment may have a yellow-orange color. Thus, it may bedesirable to add a pigment to any lotion or cream to cosmetically maskthe color imparted by the drug. Any pigment suitable for cosmetic orpharmaceutical formulations may be combined with the liposomes of thepresent disclosure. Such pigments include, but are not limited to,titanium dioxide, iron oxides, zinc oxide, combinations thereof, and thelike. In embodiments, a water-dispersible grade of titanium dioxidepowder may be used for lightening the color of the final cream. Theyellow-orange color of the cream, imparted by CoQ10, may besubstantially reduced and may be cosmetically improved by the additionof titanium dioxide in an amount of up to about 1% by weight of thelotion or cream, in embodiments from about 0.2% to about 2% by weight ofthe lotion or cream. In addition to the inorganic pigments,water-soluble or water dispersible FD&C or D&C dyes, and/or pearlescentopacifiying agents based on glyceryl stearate, or mixtures of glycerylstearate and other pearlescent agents suitable for use in topicalpharmaceutical compositions, may be utilized.

In some embodiments, the amount of preservatives utilized in acomposition of the present disclosure including a lipophilic bioactiveagent in liposomes may be reduced by the inclusion of additionaladditives including those described above. For example, the amount ofpreservatives may be reduced in a composition of the present disclosureby the addition of multifunctional diols including, but not limited to,1,2-pentane diol, 1,4-pentane diol, hexylene glycol, propylene glycol,1,3-butylene glycol, glycerol, diglycerol, combinations thereof, and thelike. In addition, the amount of preservatives may be reduced bylowering the water activity, A_(w), of the composition by the additionof humectants described above and through the addition of soluble salts,e.g., sodium lactate and lactic acid which are present in the buffer andneutralization phase of the embodiments described above.

In embodiments, other soluble ingredients may also be added tocompositions of the present disclosure to reduce the level ofpreservatives necessary. Such additional soluble ingredients include,but are not limited to, pH adjusting and buffering agents, tonicityadjusting agents, wetting agents and the like, for example, sodiumacetate, sodium chloride, potassium chloride, calcium chloride, sorbitanmonolaurate, triethanolamine oleate, and the like. Other buffers whichmay be added include sodium hydroxide, potassium hydroxide, ammoniumhydroxide, monoethanolamine, diethanolamine, triethanolamine,diisopropanolamine, aminomethylpropanol, trimethamine,tetrahydroxypropyl ethylenediamine, citric acid, acetic acid, lacticacid, and salts of lactic acid including sodium lactate, potassiumlactate, lithium lactate, calcium lactate, magnesium lactate, bariumlactate, aluminum lactate, zinc lactate, sodium citrate, sodium acetate,silver lactate, copper lactate, iron lactate, manganese lactate,ammonium lactate, combinations thereof, and the like. These additivesmay be added to any phase described above utilized in forming a cream orlotion, including the oil phase, water phase, neutralizing phase,pigment, combinations thereof, and the like.

In embodiments the use of the liposome concentrate described above informing the compositions of the present disclosure may permit tailoringthe production of various compositions having the bioactive agent atvarying concentrations. For example, in embodiments, the liposomeconcentrate may have the bioactive agent at a concentration of fromabout 10 to about 15 times greater than the amount of bioactive agent ina final composition for administration to a patient. For manufacturing,a large batch of concentrate may be produced, and then multiple portionsof the concentrate may be utilized to produce multiple compositionshaving the bioactive agent at varying concentrations. This permits greatflexibility in tailoring the concentration of a bioactive agent in acomposition of the present disclosure.

For example, in embodiments, a submicron liposome concentrate may beutilized to create a dosage range of treatment creams possessing alipophilic bioactive agent. In embodiments, the liposome concentrate maybe a CoQ10-solubilized, fluidized or emulsified within a high linoleicacid-phosphatidyicholine multilamella liposome. There are a few reasonsfor creating a liposome concentrate of lipophilic drug actives. Forexample, the creation of a drug-liposome-concentrate in its nascentform, without the addition of a cream, lotion, or other vehicles, maypermit direct measurement of the drug active, the liposome particlesize, and particle size distribution without interference from otheradditives, typically present in the final product form. For example,cream and lotion emulsions formed by the homogenization of an oil phase,a water phase, and suitable emulsifiers and coemulsifiers, as describedherein may include oil-in-water emulsion particles ranging fromsubmicron size to a preponderance of particles above one micron. Once aliposome dispersion or liposome concentrate, as described, is added tothe other components or phases of the final cream or lotion vehicle,measurement of the drug-liposome particle size and particle sizedistribution as distinguished from the particles of O/W emulsion orother additives (e.g., pigment) becomes impractical, if not impossible.

The preparation of a drug-liposome concentrate may also help maintainthe intrinsic stability and initial particle size distribution of thedrug-liposome. In the embodiments described for Coenzyme Q10 liposomeconcentrates, the concentrate can be stored at a controlled roomtemperature (59-86° F.) for several months until needed for manufacture.Once required for production, the liposome concentrate may be addedafter the formation of the emulsion vehicle and at a temperature thatwill not adversely affect the drug-liposome particles.

The preparation of the drug-liposome concentrate may also allow forassay of the drug and confirmation of stability of the drug in theliposome prior to incorporation of the liposome concentrate in the finalvehicle. Moreover, the formulation of a drug-liposome concentrate at asingle concentration allows this concentrate to be used to create a widerange of final dosage concentrations of the drug. In embodiments, thedrug-liposome concentrate of Coenzyme Q10 may contain about 21% or about22% Coenzyme Q10 and may be used to make final compositions, sometimesreferred to herein as products, containing Coenzyme Q10 in amounts fromabout 0.5% up to about 20% by weight of the final composition, inembodiments from about 0.75% by weight to about 10% by weight of thefinal composition. This range may be widened substantially depending onthe dose requirements of the lipophilic active. As noted in the Examplesbelow, in some embodiments the bioactive, such as Coenzyme Q10, may bepresent in amounts of from about 1.25% by weight of the finalcomposition to about 5% by weight of the final composition, in otherembodiments from about 1.5% by weight to about 5% by weight of thecomposition.

The resulting creams, lotions, and the like may have a long shelf-life;i.e., they may remain stable during storage for at least about 2 years,in embodiments from about 2 to about 10 years.

Such lotions and creams may be packaged in any suitable packaging withinthe purview of those skilled in the art, including metal or glaminatetubes. The resulting creams have acceptable patient use characteristicsfor aesthetic considerations of product application, e.g., acceptable“rub-in”, skin feel, product odor, product color, and product transfer.

Compositions of the present disclosure may be utilized to administerlipophilic bioactive agents for the treatment of any disease orcondition which may benefit from the application of the lipophilicbioactive agent, including those disclosed in International PublicationNo. WO 2005/069916, the entire disclosure of which is incorporated byreference herein. While the instant disclosure has discussedtopical/transdermal formulations in some detail, depending on thespecific conditions being treated, the liposomes containing lipophilicbioactive agents described above may also be formulated and administeredby other systemic and/or local routes. Suitable routes of administrationinclude, but are not limited to, other topical routes of administration,oral, rectal, inhalation, vaginal, transmucosal, intestinal, parenteralincluding intramuscular, subcutaneous, intramedullary, intrathecal,direct intraventricular, intravenous, intraperitoneal, intranasal,intraocular, intratumoral, combinations thereof, and the like.

Where the compositions are administered by injection, the compositionsmay be administered in a single bolus, multiple injections, or bycontinuous infusion (for example, intravenously or by peritonealdialysis). For parenteral administration, the compositions may beformulated in a sterilized pyrogen-free form. Compositions of thepresent disclosure can also be administered in vitro to a cell (forexample, to induce apoptosis in a cancer cell in an in vitro culture) bysimply adding the composition to the fluid in which the cell iscontained.

In some embodiments, compositions of the present disclosure may beutilized in the treatment of cancer. As used herein, “cancer” refers toall types of cancer or neoplasm or malignant tumors found in mammals,including, but not limited to: leukemias, lymphomas, melanomas,carcinomas and sarcomas.

As used herein, the terms “cancer,” “neoplasm,” and “tumor,” are usedinterchangeably and in either the singular or plural form, refer tocells that have undergone a malignant transformation that makes thempathological to the host organism.

Primary cancer cells (that is, cells obtained from near the site ofmalignant transformation) can be readily distinguished fromnon-cancerous cells by well established techniques, particularlyhistological examination. The definition of a cancer cell, as usedherein, includes not only a primary cancer cell, but any cell derivedfrom a cancer cell ancestor. This includes metastasized cancer cells,and in vitro cultures and cell lines derived from cancer cells.

When referring to a type of cancer that normally manifests as a solidtumor, a “clinically detectable” tumor is one that is detectable on thebasis of tumor mass, e.g., by procedures such as CAT scan, MR imaging,X-ray, ultrasound or palpation, and/or which is detectable because ofthe expression of one or more cancer-specific antigens in a sampleobtainable from a patient.

Examples of cancers include cancer of the brain, breast, pancreas,cervix, colon, head and neck, kidney, lung, non-small cell lung,melanoma, mesothelioma, ovary, sarcoma, stomach, uterus andMedulloblastoma.

The term “sarcoma” generally refers to a tumor which is made up of asubstance such as embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Examples of sarcomas which can be treated with thecompositions of the present disclosure include, but are not limited to,chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma,osteosarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma,ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorinecarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma,stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma,giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathicmultiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of Bcells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma,Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma,malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocyticsarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma,telangiectatic sarcoma, and the like.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and/or other organs. Melanomas which canbe treated with the compositions of the present disclosure include, butare not limited to, for example, acrallentiginous melanoma, amelanoticmelanoma, benign juvenile I melanoma, Cloudman's melanoma, S91 melanoma,Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma,malignant melanoma, nodular melanoma, subungual melanoma, superficialspreading melanoma, and the like.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues whichgive rise to metastases. Carcinomas which can be treated with thecompositions of the present disclosure include, but are not limited to,for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma,adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of theadrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cellcarcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamouscell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,bronchogenic carcinoma, cerebriform carcinoma, cholangiocellularcarcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma,corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinomacutaneum, cylindrical carcinoma, cylindrical cell carcinoma, ductcarcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma,epiermoid carcinoma, carcinoma epitheliale adenoides, exophyticcarcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniformcarcinoma, gelatinous carcinoma, giant cell carcinoma, carcinomagigantocellulare, glandular carcinoma, granulosa cell carcinoma,hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma,Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma,infantile embryonal carcinoma, carcinoma in situ, intraepidermalcarcinoma, intraepithelial carcinoma, Krompecher's carcinoma,Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma,carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma,carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinomamoue, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare,mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinomamyxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinomaossificans, osteoid carcinoma, papillary carcinoma, periportalcarcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceouscarcinoma, renal cell carcinoma of kidney, reserve cell carcinoma,carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma,carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex,small-cell carcinoma, solenoid carcinoma, spheroidal cell carcinoma,spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma,squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum,carcinoma telangiectodes, transitional cell carcinoma, carcinomatuberosum, tuberous carcinoma, verrucous carcinoma, and the like.

Additional cancers which can be treated with the compositions of thepresent disclosure include, for example, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer,ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis,primary macroglobulinemia, small-cell lung tumors, primary brain tumors,stomach cancer, colon cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary cancer, bladder cancer, premalignant skin lesions,testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophagealcancer, genitourinary tract cancer, malignant hypercalcemia, cervicalcancer, endometrial cancer, adrenal cortical cancer, prostate cancer,and the like.

In addition, and as noted above, however, the compositions of thepresent disclosure may also be utilized to administer a lipophilicbioactive agent for the treatment of any disease or condition that maybenefit from the application of a lipophilic bioactive agent.

The following Examples are being submitted to illustrate embodiments ofthe present disclosure. These Examples are intended to be illustrativeonly and are not intended to limit the scope of the present disclosure.Also, parts and percentages are by weight unless otherwise indicated.

EXAMPLES Example 1

A concentrate was produced with CoQ10 as the lipophilic bioactive agent.About 10 kilograms (kg) of polysorbate 80 was placed in a vacuum kettleand heated to a temperature of from about 50° C. to about 55° C. About8.8 kg of CoQ10 was combined with the PHOSPHOLIPON® 85G, a vacuum wasapplied with the temperature maintained at from about 50° C. to about55° C., and the contents mixed for about 15 minutes. The resultingmaterial may be referred to herein as the CoQ10 phase or the firstphase. The CoQ10 was dissolved in the polysorbate 80 with the vacuumkettle sealed, vacuum on, and temperature of the mix ofpolysorbate/CoQ10 from about 50° C. to about 55° C.

In a separate kettle, about 15.8 kg of water was heated to a temperatureof from about 50° C. to about 55° C., and about 0.2 kg of phenoxyethanoland about 2 kg of HYDROLITE-5@ pentylene glycol were added and mixeduntil clear and uniform. About 8 kg of PHOSPHOLIPON® 85G was then addeduntil dispersed. The resulting material may be referred to herein as thewater phase or the second phase. The water phase achieved a uniformdispersion and hydration of the lecithin and was added to theCoQ10/Polysorbate liquid as described below at a temperature from about50° C. to about 55° C.

A Silverson in-line production scale homogenizer, similar to theSilverson L4RT model used for laboratory scale batches, was utilized tocombine the two phases described above, i.e., the CoQ10 phase and thewater phase. Homogenization occurred using the Silverson standardemulsion head screen by mixing at full capacity (from about 7000 rpm toabout 10,000 rpm) for a total of about 5 minutes through a closedrecirculating loop and under vacuum (from about 18 mm to about 20 mm Hg)at temperatures of from about 50° C. to about 55° C. with sweepagitation until the solubilized CoQ10 was completely encapsulated anduniformly dispersed thereby creating a thick, uniform liposomaldispersion. The resulting CoQ10 concentrate possessed CoQ10 at aconcentration of about 22% by weight. The PHOSPHOLIPON® 85Gconcentration was about 8% by weight of the total composition, that is,of the combination of the two phases described above.

In separate experiments, a one kg laboratory batch of the 22% CoQ10concentrate described above was produced and samples were taken at 5minute intervals during homogenization. The particle size of theliposomes at the various sampling times was determined utilizing laserdiffraction equipment (Malvern 2000) following the manufacturer'sdirections. Details of the homogenization process and the particle sizesobtained during homogenization are set forth below in Table 1.

TABLE 1 Avg. Approx. Process Silverson particle Particle peak temp. timeL4RT Head diameter Intensity; exposure (minutes) Speed (nm) % < 300 nm(° C.) 5 7000 108 84.9 55 10 7000 162 57.8 65 15 7000 112 85.4 55 207000 149 67.0 62 30 7000 120 83.0 55 45 7000 107 85.0 55As can be seen from Table 1, the CoQ10 concentrate formula and processdescribed above was capable of producing liposomes with an averagediameter of 107 nm and a particle distribution that included 85% of allliposomes produced within a size of from about 59 nm to about 279 nm. Ashort process time (about 5 minutes) produced a liposome dispersion ofCoQ10 just as efficiently as a long process time (about 45 minutes). Ascan also be seen from the above, optimal liposome particles wereobtained where the CoQ10 was not exposed to temperatures above about 55°C.

Example 2

A cross linked acrylic acid polymer dispersion was prepared for use as aviscosity agent in a cream composition. The acrylic acid utilized,CARBOMER 940, was prepared in a 2% dispersion with the followingcomponents set forth below in Table 2:

TABLE 2 Amount Phase Trade Name CTFA Name Percent (Kg) 1 phenoxyethanolphenoxyethanol 0.500 0.0750 1 hydrolite-5 pentylene glycol 5.000 0.75002 purified water, USP water 92.500 13.8750 3 ACRITAMER 940 CARBOMER 9402.000 0.3000 Totals 100.000 15.0000

The manufacturing process was conducted as follows. The equipment wasfirst cleaned and sanitized. On a benchtop, the phase 1 ingredients weremixed until clear and uniform. The required amount of water (phase 2)was weighed and added to a phase vessel kettle of the homogenizerdescribed above in Example 1. The water was heated with a hotwater/steam jacket to a temperature of from about 60° C. to about 65° C.Phase 1 was then added to the phase 2 water with moderate agitationuntil clear and uniform. The phase 1 container was rinsed with processwater and the temperature was maintained at from about 60° C. to about65° C. The agitator was then turned on high and CARBOMER 940 powder(phase 3) was added.

The temperature was maintained at from about 60° C. to about 65° C. andmixing continued at medium-high speed of from about 500 rpm to about 800rpm until all the CARBOMER 940 powder was added. The CARBOMER powder wasadded slowly to the vortex of the mixture of phases 1 and 2. The powderwas hand sifted slowly so that the total amount of CARBOMER was added inno less than about 10 minutes.

Mixing continued at medium-high agitation until all powder wasthoroughly dispersed and no “fish-eyes” were present. The manufacturingprocess was conducted so that all of the unneutralized CARBOMER 940powder was completely dispersed to create a smooth translucentdispersion of fully hydrated CARBOMER polymer. Agitation of the batchwas high enough to create a visible vortex, but not so high to causesplashing of the batch. Adequate mixing of the batch occurred at a highspeed of from about 800 rpm to about 1300 rpm over a period of time fromabout 60 minutes to about 90 minutes. The batch temperature wasmaintained at from about 60° C. to about 65° C. at the start of mixingand from about 55° C. to about 65° C. during mixing. The elevatedtemperature assisted in dispersion of the CARBOMER polymer and helpedprevent agglomeration.

The batch was cooled to from about 25° C. to about 30° C. with chilledwater through a jacket and mixing continued with medium-high agitation.Samples were taken to determine microquality, pH, specific gravity andviscosity.

Example 3

A cream emulsion base was formed utilizing several phases forcombination with the CoQ10 concentrate possessing liposomes ofExample 1. Phases A, B, C and D were combined to form the base cream.Phase E was the CoQ10 concentrate of Example 1 (22% w/w CoQ10). Detailsof the preparation of the cream emulsion base and the subsequentaddition of the CoQ10 concentrate of Example 1 are set forth below.

For preparation of the cream possessing CoQ10 at 1.5% by weight, theprocedure for combining the various phases was as follows with theingredients set forth below in Tables 3-7:

TABLE 3 CoQ10 Cream 1.5% Amount Phase Trade Name CTFA Name Percent (g) ARITAMOLLIENT C12-15 ALKYL 5.000 1.0000 TN BENZOATE A RITA CA CETYL 2.5000.5000 ALCOHOL A RITA SA STEARYL 2.000 0.4000 ALCOHOL A RITAPRO GLYCERYL4.500 0.9000 165 STEARATE AND PEG-100 STEARATE

Phase A (the “Oil Phase”) included C12-15 alkyl benzoates, which arelight esters added for emolliency and spreadability. The cetyl alcoholand stearyl alcohol were waxes added to impart body or texture to thecream and the glyceryl stearate and PEG-100 stearate mixture was aprimary emulsifier included to form an oil-in-water (o/w) emulsion. On abenchtop, the Phase A ingredients were weighed in a vacuum kettle andheated to from about 70° C. to about 75° C. in water bath.

TABLE 4 Amount Phase Trade Name CTFA Name Percent (g) B RITA GLYCERINglycerin 2.000 0.4000 B HYDROLITE-5 pentylene glycol 2.125 0.4250 BTRANSCUTOL P ethoxydiglycol 5.000 1.0000 B phenoxyethanol phenoxyethanol0.463 0.0926 B ACRITAMER 940, water, CARBOMER 50.000 10.0000 2%dispersion 940 B purified water USP Water 11.000 2.2000

Phase B (the “Water Phase”), contained glycerine for skin moisturizationand humectancy; pentylene glycol for humectancy, to aid in skinpenetration and to improve the microbiological preservation profile;ethoxydiglycol to enhance CoQ10 skin penetration of the liposomes;phenoxyethanol for microbiological preservation; purified water as thephase solvent, and CARBOMER 940 dispersion of Example 2 above to controlthe rheological properties of the cream formulas and to add stability tothe primary emulsion.

Phase B ingredients were placed in a separate vacuum mixing kettle. Theingredients were mixed with moderate sweep mixing while heating to fromabout 70° C. to about 75° C. (no vacuum). When the Phase B ingredientsreached from about 70° C. to about 75° C., Phase A ingredients wereadded at from about 70° C. to about 75° C. with moderate sweep mixing.The mixture of Phases A and B was recirculated through a Silversonhomogenizer as described above in Example 1 (standard head) andcontinued to the next part of the process.

TABLE 5 Amount Phase Trade Name CTFA Name Percent (g) C TEALAN 99%triethanolamine 1.300 0.2600 C RITALAC lactic acid 0.300 0.0600 LA USP CRITALAC Sodium lactate, 2.000 0.4000 NAL water C distilled water Water3.312 0.6624

In Phase C (the “Neutralization and Buffer Phase”), purified water actedas a solvent and a diluent for the other ingredients in this phase.Triethanolamine was the primary neutralizer of the CARBOMER acrylic acidcopolymer in the water phase (Phase B); sodium lactate solution (60% w/win water) and lactic acid were added as a buffer system to adjust andmaintain the final pH of the cream from about 5 to about 5.5, which iswithin the natural pH range of the skin.

On a benchtop, Phase C ingredients were weighed and mixed until uniformand heated to from about 60° C. to about 65° C. The Phase C mixture wasthen added to the vacuum mixing kettle containing Phases A and B withsweep mixer on medium-high.

Mixing continued while moving to the next part of the process.

TABLE 6 Amount Phase Trade Name CTFA Name Percent (g) D TITANIUMtitanium 1.000 0.2000 DIOXIDE, #3328 dioxide

Phase D (the “Pigment Phase”). A water-dispersible grade of TitaniumDioxide powder was used in the formula solely for the purpose oflightening the color of the final cream color. The yellow-orange colorof the cream, imparted by CoQ10, was substantially reduced andcosmetically improved by the addition of about 1% w/w Titanium Dioxide.

For Phase D of the process, weighed TiO2 was added to the batch (PhasesA, B and C) and mixed and recirculated through the Silverson homogenizer(high shear head) for about 10 minutes or until completely uniform andfully extended (color was checked to confirm).

It was important to insure there was no agglomeration or clumping of thetitanium dioxide on the sweep mixing blades; this was confirmed byvisual inspection. A Silverson in line homogenizer as described above inExample 1 was used with a high shear screen to insure maximumdeagglomeration and grinding of the titanium dioxide. The finaldispersion of the titanium dioxide was checked with a Hegman PH-175fineness of grind gauge.

TABLE 7 Amount Phase Trade Name CTFA Name Percent (g) E CoQ10 WATER,7.500 1.5000 CONCENTRATE POLYSORBATE 80, 22% (From UBIQUINONE, Example 1LECITHIN, above) PENTYLENE GLYCOL, PHENOXYETHANOL Totals 100.000 20.000

Recirculation was stopped and the batch was cooled to from about 50° C.to about 55° C. with the sweep mixer on medium, at a speed of about 30rpm. The previously weighed CoQ10 concentrate (Phase E) from Example 1was warmed to from about 45° C. to about 50° C. and added to the batch(Phases A, B, C and D).

All phases were mixed with sweep agitation at about 60 rpm with a vacuumapplied until uniform. Temperature was maintained at about 50° C.

The batch was cooled to from about 35° C. to about 45° C. with mixing atabout 60 rpm and the application of a vacuum.

The resulting material was placed into holding containers.

For preparation of a cream possessing CoQ10 at 3% by weight, the exactsame procedure described above for forming the cream possessing CoQ10 at1.5% by weight was followed. The materials for each phase, and theamounts utilized, are set forth below in Tables 8-12:

TABLE 8 CoQ10 Cream 3% Amount Phase Trade Name CTFA Name Percent (g) ARITAMOLLIENT C12-15 alkyl 4.000 0.8000 TN benzoate A RITA CA cetylalcohol 2.500 0.5000 A RITA SA stearyl alcohol 2.000 0.4000 A RITAPRO165 glyceryl stearate 4.500 0.9000 and PEG-100 stearate

TABLE 9 Amount Phase Trade Name CTFA Name Percent (g) B RITA GLYCERINglycerin 2.000 0.4000 B HYDROLITE-5 pentylene glycol 2.250 0.4500 BTRANSCUTOL P ethoxydiglycol 5.000 1.0000 B phenoxyethanol phenoxyethanol0.463 0.0926 B ACRITAMER 940, water, CARBOMER 40.000 8.0000 2%dispersion 940 B purified water, USP water 15.000 3.0000

TABLE 10 Amount Phase Trade Name CTFA Name Percent (g) C TEALAN 99%triethanolamine 1.300 0.2600 C RITALAC LA Lactic acid 0.500 0.1000 CRITALAC NAL sodium lactate, water 2.000 0.4000 C purified water, water2.487 0.4974 USP

TABLE 11 Amount Phase Trade Name CTFA Name Percent (g) D TITANIUMtitanium dioxide 1.000 0.2000 DIOXIDE, #3328

TABLE 12 Amount Phase Trade Name CTFA Name Percent (g) E CoQ10 water,15.000 3.0000 CONCENTRATE POLYSORBATE 80, 22% ubiquinone, LECITHIN,(From Example 1 pentylene glycol, above) phenoxyethanol Totals 100.00020.000

A similar cream was prepared by using the 22% CoQ10 concentrate fromExample 1 in an amount of about 25% by weight to create a cream havingCoQ10 at a concentration of about 5% by weight.

A summary of the contents of CoQ10 creams having 1.5% CoQ10 by weight,3% CoQ10 by weight, and 5% CoQ10 by weight are set forth below in Tables13, 14 and 15 respectively. Note that in all the formulation examplesgiven above and below for CoQ10 creams, the amount of concentrate usedwould actually yield a final theoretical concentration of about 10%above the target concentration. So, for “CoQ10 Cream, 1.5%”, the actualbatch amount used was 7.5% by weight of a 22% by weight concentrate thatyielded 1.65% w/w CoQ10. The “CoQ10 Cream, 3%” was made with 15% byweight of the 22% by weight CoQ10 concentrate that yielded a theoreticalcontent of 3.3% CoQ10 by weight. The 10% excess drug was added to extendthe overall shelf life of the product and maintain the drug content fromabout 90% to about 110% of the label or expected drug content.

TABLE 13 CoQ10 CREAM, 1.5% Phase Trade Name INCI Name Percent Supplier ARITAMOLLIENT C12-15 alkyl 5.000 RITA TN benzoates A RITA CA cetylalcohol 2.000 RITA A RITA SA stearyl alcohol 1.500 RITA A RITAPRO 165glyceryl 4.500 RITA stearate and PEG-100 stearate B RITA Glycerine 2.000RITA GLYCERINE B HYDROLITE 5 pentylene 2.125 SYMRISE glycol B TRANSCUTOLEthoxydiglycol 5.000 GATTEFOSSE' P B phenoxyethanol Phenoxy- 0.463 RITAethanol B PURIFIED deionized 11.000 WATER water B ACRITAMER water,pentyl- 50.000 940 dispersion, ene glycol, 2% CARBOMER 940, phenoxy-ethanol C purified water water 4.212 USP C triethanolaminetriethanolamine 1.300 RITA C RITALAC NAL sodium lactate 2.000 RITA andwater C RITALAC LA lactic acid 0.400 RITA USP D TITANIUM titanium 1.000MPSI DIOXIDE #3328 dioxide E CoQ10 liposome water, 7.500 concentrate,POLY- 22% W/W (From SORBATE 80, Example 1) ubiquinone, lecithin,pentylene glycol, phen- oxyethanol Totals 100.000

TABLE 14 CoQ10 Cream 3% Phase Ingredient % w/w A C12-C15 Alkyl Benzoate4.000 A Cetyl Alcohol 2.000 A Stearyl Alcohol 1.500 A Glyceryl Strearate& PEG 100 Stearate 4.500 B Glycerin 2.000 B Pentylene Glycol 2.250 BEthoxydiglycol 5.000 B Phenoxyethanol 0.476 B Carbomer 40.000 B PurifiedWater 16.000 C Sodium Lactate 2.000 C Purified Water 2.474 CTriethanolamine 1.300 C Lactic Acid 0.500 D Titanium Dioxide 1.000 ECoQ10 Concentrate 22% (From Example 1) 15.000 Total: 100.000

TABLE 15 CoQ10 Cream 5% Phase Ingredient % w/w A C12-C15 Alkyl Benzoate3.000 A Cetyl Alcohol 2.000 A Stearyl Alcohol 1.500 A Glyceryl Strearate& PEG 100 Stearate 4.500 B Glycerin 2.000 B Pentylene Glycol 2.000 BEthoxydiglycol 5.000 B Phenoxyethanol 0.450 B Carbomer 35.000 B PurifiedWater 14.000 C Sodium Lactate 2.000 C Purified Water 0.750 CTriethanolamine 1.300 C Lactic Acid 0.500 D Titanium Dioxide 1.000 ECoQ10 Concentrate 22% (From Example 1) 25.000 Total: 100.000Note: 10% manufacturing overage of CoQ10 was added to the 1.5%, 3% and5% batches (i.e., 1.5% plus 0.15%, 3% plus 0.3%, and 5% plus 0.5%).

Example 4

Creams possessing CoQ10 produced in Example 3 (i.e., 1.5%, 3%, and 5%)above were applied to porcine skin. The topical dose study was conductedon two pigs each, one male and one female. Each animal had 6 test areas;three test areas on each side. For each pig, one side (3 sites) wasdosed once per day for 7 days, while the opposite test side (3 testareas) for each pig was dosed only one time on day 1. The creams fromExample 3, prepared with ethoxydiglycol, were used on the male animals.The female animals received 3 test formulas that contained the sameingredients as the samples produced in Example 3 above, except theycontained 5% 1,3-butylene glycol instead of 5% ethoxydiglycol. Detailsof these formulations made with 1,3-butylene glycol, which possessed1.5% CoQ10 by weight, 3% CoQ10 by weight and 5% CoQ10 by weight, are setforth below in Tables 16, 17, and 18 respectively.

TABLE 16 CoQ10 Cream 1.5% Nominal Active Butylene Glycol Base PhaseIngredient % w/w A C12-C15 Alkyl Benzoate 5.000 A Cetyl Alcohol 2.000 AStearyl Alcohol 1.500 A Glyceryl Strearate & PEG 100 Stearate 4.500 BGlycerin 2.000 B Pentylene Glycol 2.125 B Butylene Glycol 5.000 BPhenoxyethanol 0.463 B Carbomer 50.000 B Purified Water 11.001 C SodiumLactate 2.000 C Purified Water 4.211 C Triethanolamine 1.300 C LacticAcid 0.400 D Titanium Dioxide 1.000 E CoQ10 Concentrate 22% (FromExample 1) 7.500 Total: 100.000

TABLE 17 CoQ10 Cream 3% Nominal Active Butylene Glycol Base PhaseIngredient % w/w A C12-C15 Alkyl Benzoate 4.000 A Cetyl Alcohol 2.000 AStearyl Alcohol 1.500 A Glyceryl Strearate & PEG 100 Stearate 4.500 BGlycerin 2.000 B Pentylene Glycol 2.250 B Butylene Glycol 5.000 BPhenoxyethanol 0.476 B Carbomer 40.000 B Purified Water 16.000 C SodiumLactate 2.000 C Purified Water 2.474 C Triethanolamine 1.300 C LacticAcid 0.500 D Titanium Dioxide 1.000 E CoQ10 Concentrate 22% (FromExample 1) 15.000 Total: 100.000

TABLE 18 CoQ10 Cream 5% Nominal Active Butylene Glycol Base PhaseIngredient % w/w A C12-C15 Alkyl Benzoate 3.000 A Cetyl Alcohol 2.000 AStearyl Alcohol 1.500 A Glyceryl Strearate & PEG 100 Stearate 4.500 BGlycerin 2.000 B Pentylene Glycol 2.000 B Butylene Glycol 5.000 BPhenoxyethanol 0.450 B Carbomer 35.000 B Purified Water 14.000 C SodiumLactate 2.000 C Purified Water 0.750 C Triethanolamine 1.300 C LacticAcid 0.500 D Titanium Dioxide 1.000 E CoQ10 Concentrate 22% (FromExample 1) 25.000 Total: 100.000

All animals received the same dose of each formulation, which was 200mg, to a 121 cm² application area applied once or daily for 7 days.

After application, skin samples were obtained and analyzed as follows.The skin test area was gently washed with a mild soap and water mixture(e.g., 1% Ivory Soap in water or equivalent) to remove any residualtopical test formulation. If the area to be excised was larger than thedosed area, the dosed area was demarked with indelible ink to delineatethe skin area that was dosed. A full thickness skin section was removedby scalpel with a size approximating 10 cm×10 cm, to the depth andincluding the adipose layer. Following excision, the skin section waslaid flat and wrapped in two layers of plastic wrap (SARAN WRAP™ orequivalent), and frozen to about −70° C. or colder in a timely manner.Each skin section was identified as appropriate (e.g. animalidentification, study number, date, etc.). Samples were maintained atabout −70° C. or lower until examined.

Each skin section was placed in a watertight plastic bag and thawed infrom about 30° C. to about 35° C. water baths. Once thawed, each skinsection was gently rinsed with distilled deionized water to remove anyresidual surface dose and blood. All subcutaneous tissue (e.g. adipose)was removed by scalpel to the level of the papular dermis.

Each skin section was then tape stripped (TRANSPORE™, from 3M) fromabout 10 to about 20 times until approximately 10-25% surface glisteningwas observed. This process removed the stratum corneum and any residualsurface dose.

On each full skin sheet, 6 areas were demarcated with ink. Thedemarcated areas were 1 cm² in area.

Each skin section was placed in a watertight plastic bag and immersed ina ˜65° (±3°) C water bath to initiate the separation process of theepidermis from the dermis. The test sites were then excised from theskin sheet by punch, and the epidermis removed from the dermis byforceps. The individual skin sections were weighed and the weightrecorded. The individual skin sections were minced with a scalpel,placed into pre-labeled tubes, and saved for subsequent analysis.

The skin samples were extracted in isopropanol (IPA) on a shaker forabout 47 hours, then stored at about −20° C. until further processed.The samples were then centrifuged at about 13,500 rpm for about 10minutes and the supernatant was collected into 2 mL amber vials.

Quantification of CoQ10 was performed by High Performance LiquidChromatography (HPLC-UV). Briefly, HPLC was conducted on aHewlett-Packard 1100 Series HPLC system with an Agilent 1100 SeriesLC/MSD. A solvent system including about 65% Ethanol and about 35%Methanol was run through an Aquasil C18 column (about 3 mm×about 100 mm,5p) at a flow rate of about 1 mL/min. Ten microliters of sample wereinjected. Peak areas were quantified to concentration using an externalstandard curve prepared from the neat standard. The curve was spikedinto IPA due to solubility issues of CoQ10 in water.

The results for the content of CoQ10 in mini-pig skin are summarized inFIGS. 1 and 2 , and Tables 19 and 20 below. The 6 replicates per skinsection were corrected to tissue weight and averaged to obtain a meanfor each dosed site.

TABLE 19 Mean ± SD Tissue Weight (n = 42) Donor # Epidermis (grams)Dermis (gm) 5061873 (Male) 0.037 ± 0.012 0.682 ± 0.129 5061521 (Female)0.026 ± 0.007 0.603 ± 0.090

TABLE 20 Mean: ±SD Measured Concentration of CoQ10 in Porcine Skin (n =6/section) Dose Epidermis Dermis Donor # Sex Side (mg) (μg/gm) (μg/gm)5061873 Male Left 1.5 137.7 ± 58.2 0.72 ± 1.12 5061873 Male Left 3.0188.7 ± 40.3 <LLQ 5061873 Male Left 5.0 163.4 ± 39.1 0.16 ± 0.39 5061873Male Right 1.5  519.3 ± 101.2 0.93 ± 0.81 5061873 Male Right 3.0  315.3± 227.0 <LLQ 5061873 Male Right 5.0  331.2 ± 128.7 <LLQ 5061873 MaleCenter 0  24.6 ± 11.5 <LLQ 5061521 Female Left 1.5 135.6 ± 39.2 <LLQ5061521 Female Left 3.0 211.8 ± 60.5 <LLQ 5061521 Female Left 5.0 211.9± 67.8 <LLQ 5061521 Female Right 1.5 118.4 ± 32.6 <LLQ 5061521 FemaleRight 3.0  84.7 ± 24.6 <LLQ 5061521 Female Right 5.0 118.1 ± 26.6 <LLQ5061521 Female Center 0  25.7 ± 21.8 <LLQ <LLQ = below lower level ofquality validation range (i.e., not detected)

The data indicated that measurable amounts of CoQ10 were observed in allepidermal samples and in selected dermal samples.

All dosed sites for the epidermis were found to contain CoQ10 at levelsthat were significantly greater than the non-dosed sites (p<0.001).

There were no significant differences between the epidermal contents forCoQ10 across the three dosing concentrations in either the male orfemale pig skin sections (p>0.02)

Between the male and female pig, for the sites from the animal's rightside (1-day dosing), the epidermal content for the 1.5% CoQ10 and 5%CoQ10 applied doses from the male's skin was significantly greater thanthat seen in the female's skin (p<0.003), but not for the 3% CoQ10 dose(p=0.0329). Thus, as can be seen from the data, the penetration of theCoQ10 on a single dose basis was significantly greater for theethoxydiglycol formula vs. the butylene glycol formula (p<0.003 for the1.5% and 5% doses and p=0.0329 for the 3% dose).

The epidermal levels for both male and female skin sections, for allthree dose applications, for the 7-day dosing period (left side), werestatistically identical.

Dermal content was only observed in the male skin sections for the 1.5%CoQ10 and 5% CoQ10 dose applications from the 7-day dosing period (leftside), and the 1.5% CoQ10 dose application from the 1-day dosing period(right side).

A summary of the data is provided as follows in Table 21:

TABLE 21 % Concentration 1.5 3 5 μg drug/mg formulation 15 30 50 Amountapplied (mg): 200 200 200 Total drug applied (μg) 3000 6000 10000 Areaapplied (cm2) 121 121 121 μg Drug/cm² 24.79 49.59 82.64 Male Left side(x7 d) Epidermis (μg/cm²) 3.470 6.688 7.311 % Dose/cm² 14.0 13.5 8.8Dermis (μg/cm²) 0.575 0 0.106 % Dose/cm² 2.3 0.0 0.1 Male Right side (x1d) Epidermis (μg/cm²) 18.309 8.215 10.986 % Dose/cm² 73.8 16.6 13.3Dermis (μg/cm²) 0.582 0 0 % Dose/cm² 2.3 0.0 0.0

If one were to extrapolate the data from Table 21 to the total area ofskin, the penetration of the CoQ10 would be as set forth below in Table22.

TABLE 22 If expanded out to total area: 1.5 3 5 Epidermis (μg/121 cm²)419.87 809.248 884.631 % Dose 14.0 13.5 8.8 Epidermis (μg/121 cm²)2215.389 994.015 1329.306 % Dose 73.8 16.6 13.3

A single application of the CoQ10 cream formulation delivered an averageof 12%, 17%, or 70% of the applied dose for the respective 5%, 3%, and1.5% CoQ10 cream formulations. In general, the penetration of the CoQ10on a single dose basis was significantly greater for the ethoxydiglycolformula vs. the butylene glycol formula (p<0.003 for the 1.5% and 5%doses and p=0.0329 for the 3% dose). The data indicated that there was arise in epidermal content with applied concentration to 3% CoQ10 withthe 5% CoQ10 dose being essential equal to the 3% CoQ10 dose. Thissuggests that the skin became saturated with CoQ10 at the 3% CoQ10 dose,or that the vehicle was unable to deliver more CoQ10 above the 3% CoQ10concentration. It can be seen that the levels achieved in the skinfollowing 7 days of topical application were identical between the 2animals.

For the ethoxydiglycol formulations, and for the single applicationdata, average penetration of 73.8%, 16.6%, and 13.3% for the respective1.5%, 3% and 5% ethoxydiglycol containing creams was obtained.

An interesting and unexpected finding was the disproportional amount ofCoQ10 found in the epidermis for the 1.5% cream, the lowest dose ofCoQ10 tested. Without wishing to be bound by any theory, this enhancedpenetration of CoQ10 may be a function of the ratio of CoQ10 toethoxydiglycol in the cream formulations, or may possibly be related tothe ratio of ethoxydiglycol to CoQ10 and the phospholipid liposome. Therelatively higher ratio of ethoxydiglycol to CoQ10 used in the creamcontaining a lower concentration of CoQ10 may be responsible for thehigher amounts of CoQ10 found in the epidermis.

The 1.5% cream and 3% cream also successfully completed 9 weeksaccelerated testing (storage at about 35° C. and about 50° C.); passed 5freeze-thaw cycles packaged in both plastic jar and metal tubepackaging; and passed USP microbiological challenge testing. Resultswere confirmed for the same system with multiple development batches andat 1.5%, 3% and 5% by weight concentrations of CoQ10 in the creamprototype formulation base.

Example 5

Creams were produced as described in Example 3 above, except propyleneglycol was utilized instead of pentylene glycol. A concentrate was firstproduced as described in Example 1 above, with the components listedbelow in Table 23:

TABLE 23 Batch Formula - CoQ10 Concentrate Raw Material TheoreticalQuantity Phase Name % w/w kg A Polysorbate 80 NF 25.000 5.000 AUbidecarenone USP 21.000 4.200 B Propylene Glycol USP 10.000 2.000 BPhenoxyethanol NF 0.500 0.100 C Purified Water USP 35.500 7.100 CLecithin NF 8.000 1.600 Totals 100.000 20.000

The resulting CoQ10 concentrate possessed CoQ10 at a concentration ofabout 21% by weight.

A CARBOMER dispersion was prepared as described in Example 2 above foruse in forming the cream with the components listed below in Table 24:

TABLE 24 Batch Formula - Carbomer Dispersion Raw Material TheoreticalQuantity Phase Name % w/w Kg A Phenoxyethanol NF 0.500 0.0900 APropylene Glycol USP 5.000 0.9000 B Purified Water USP 92.500 16.6500 CCarbomer 940 NF 2.000 0.3600 Totals 100.000 18.000

A cream having 1.5% by weight CoQ10 and another cream having 3% byweight CoQ10 were prepared as described above in Example 3, with thecomponents listed below in Tables 25 and 26:

TABLE 25 Batch Formula - CoQ10 Cream 1.5% Raw Material TheoreticalQuantity Phase Name % w/w kg A AlkylC12-15BenzoateNF 5.000 1.000 A CetylAlcohol NF 2.000 0.400 A Stearyl Alcohol NF 1.500 0.300 A GlycerylStearate/PEG-100 Stearate 4.500 0.900 B Glycerin USP 2.000 0.400 BPropylene Glycol USP 1.750 0.350 B Diethylene Glycol Monoethyl Ether NF5.000 1.000 B Phenoxyethanol NF 0.463 0.093 B Carbomer Dispersion, 2%50.000 10.000 B Purified Water USP 8.377 1.675 B Purified Water USP (forrinsing) 3.000 0.600 C Trolamine NF 1.300 0.260 C Lactic Acid USP 0.4000.080 C Sodium Lactate Solution USP, 60% 2.000 0.400 C Purified WaterUSP 4.210 0.842 D Titanium Dioxide USP 1.000 0.200 E CoQ10 Concentrate,21% 7.500 1.500 Totals 100.00 20.00

TABLE 26 Batch Formula - CoQ10 Cream 3% Raw Material TheoreticalQuantity Phase Name % w/w kg A AlkylC12-15BenzoateNF 4.000 0.800 A CetylAlcohol NF 2.000 0.400 A Stearyl Alcohol NF 1.500 0.300 A GlycerylStearate/PEG-100 Stearate 4.500 0.900 B Glycerin USP 2.000 0.400 BPropylene Glycol USP 1.500 0.300 B Diethylene Glycol Monoethyl Ether NF5.000 1.000 B Phenoxyethanol NF 0.475 0.095 B Carbomer Dispersion, 2%40.000 8.000 B Purified Water USP 13.725 2.745 B Purified Water USP (forrinsing) 3.000 0.600 C Trolamine NF 1.300 0.260 C Lactic Acid USP 0.5000.100 C Sodium Lactate Solution USP, 60% 2.000 0.400 C Purified WaterUSP 2.500 0.500 D Titanium Dioxide USP 1.000 0.200 E CoQ10 Concentrate,21% 15.000 3.000 Totals 100.000 20.000

It will be appreciated that various of the above-disclosed and otherfeatures and functions, or alternatives thereof, may be desirablycombined into many other different systems or applications. Also thatvarious presently unforeseen or unanticipated alternatives,modifications, variations or improvements therein may be subsequentlymade by those skilled in the art which are also intended to beencompassed by the following claims.

1. A composition comprising: a liposomal concentrate comprising aphospholipid selected from the group consisting of lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidylglycerol, phosphatidic acid,phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, and combinations thereof; at least onelipophilic bioactive agent; and at least one solubilizer; in combinationwith at least one pharmaceutically acceptable carrier possessing atleast one permeation enhancer in an amount from about 0.5% by weight toabout 20% by weight of the composition, wherein the phospholipid ispresent in the composition in an amount from about 2% to about 20% byweight of the composition and the bioactive agent is present in anamount from about 0.5% to about 20% by weight of the composition.
 2. Thecomposition of claim 1, wherein the phospholipid further comprises asolvent selected from the group consisting of water, purified water,deionized water, ethanol, isopropanol, glycols, diglycols, polyglycols,and combinations thereof.
 3. The composition of claim 1, wherein thephospholipid is in combination with an additional component selectedfrom the group consisting of absorbents, antifoaming agents, acidifiers,alkalizers, buffers, antimicrobial agents, antioxidants, binders,solubilizing agents, solvents, viscosity modifiers, humectants,thickening agents, and combinations thereof.
 4. The composition of claim1, wherein the at least one lipophilic bioactive agent is selected fromthe group consisting of analgesics, anti-inflammatory agents,anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viralagents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensiveagents, anti-malarials, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, erectile dysfunction improvement agents,immunosuppressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, cox-2inhibitors, leucotriene inhibitors, macrolides, muscle relaxants,nutritional agents, opioid analgesics, protease inhibitors, sexhormones, stimulants, muscle relaxants, anti-osteoporosis agents,anti-obesity agents, cognition enhancers, anti-urinary incontinenceagents, nutritional oils, anti-benign prostate hypertrophy agents,essential fatty acids, non-essential fatty acids, and combinationsthereof.
 5. The composition of claim 1, wherein the at least onelipophilic bioactive agent is selected from the group consisting ofacutretin, albendazole, albuterol, aminogluthemide, amiodarone,amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone,azithromycin, baclofen, beclomethsone, benezepril, benzonatate,betamethasone, bicalutanide, budesonide, bupropion, busulphan,butenafine, calcifediol, calciprotiene, calcitriol, camptothecan,candesartan, capsaicin, carbamezepine, carotenes, celecoxib,cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cilostazol,cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin,clemastine, clomiphene, clomipramine, clopidrogel, codeine, coenzymeQ10, cyclobenzaprine, cyclosporine, danazol, dantrolene,dexchlopheniramine, diclofenac, dicoumarol, digoxin,dihydroepiandrosterone, dihydroergotamine, dihydrotachysterol,dirithromycin, donepezil, efavirenz, eposartan, ergocalciferol,ergotamine, essential fatty acid sources, etodolac, etoposide,famotidine, fenofibrate, fentanyl, fexofenadine, finasteride,flucanazole, flurbiprofen, fluvastatin, fosphenylion, frovatriptan,furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide,glyburide, glymepride, griseofulvin, halofantrine, ibuprofen,irbesartan, irinotecan, isosorbide dinitrate isotreinoin, itraconazole,ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole,leflunomide, lisinopril, loperamide, loratadine, lovastatin,L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone,mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole,metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone,montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir, nifedipine,nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole,oprevelkin, osteradiol, oxaprozin, paclitaxel, paricalcitol, paroxetine,pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone,probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole,raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone,ritanovir, rizatriptan, rosigiltazone, saquinavir, sertraline,sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone,sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin,tazarotene, telmisartan, teniposide, terbinafine, terzosin,tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran, tizanidine,topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone,trovafloxacin, valsartan, venlafaxine, vertoporfin, vigabatrin, vitaminA, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan,zolpidem, zopiclone, and combinations thereof.
 6. The composition ofclaim 1, wherein the pharmaceutically acceptable carrier is selectedfrom the group consisting of solvents, buffers, antioxidants,antibacterial agents, antifungal agents, stabilizing excipients,absorption enhancing agents, absorption delaying agents, hydrophilicpolymers, peptides, proteins, monosaccharides, disaccharides,carbohydrates, chelating agents, sugar alcohols, surfactants, andcombinations thereof.
 7. The composition of claim 1, wherein the atleast one permeation enhancer is selected from the group consisting ofethoxydiglycol, 1,3-butylene glycol, isopentyl diol, 1,2-pentane diol,propylene glycol, 2-methyl propan-2-ol, propan-2-ol,ethyl-2-hydroxypropanoate, hexan-2,5-diol, di(2-hydroxypropyl)ether,pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether,2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycoldipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol,polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol,dioctyl adipate, dicapryl adipate, diisopropyl adipate, diisopropylsebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctylsebacate, dibuyl suberate, dioctyl azelate, dibenzyl sebacate, dibutylphthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butylmyristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethylcaproate, ethyl salicylate, isopropyl palmitate, ethyl laurate,2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzylbenzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate,butyl stearate, benzyl salicylate, 2-hyroxyoctanoic acid, dimethylsulphoxide, methyl sulfonyl methane, n,n-dimethyl acetamide,n,n-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone,5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone,1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters,tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,1-dodecylazacyloheptan-2-one, and combinations thereof.
 8. Thecomposition of claim 1, wherein the permeation enhancer is present in anamount from about 3% by weight to about 15% by weight of the compositionand the bioactive agent is present in an amount of from about 0.75% byweight to about 10% by weight of the composition.
 9. The composition ofclaim 1, wherein the solubilizer is selected from the group consistingof polyoxyalkylene dextrans, fatty acid esters of saccharose, fattyalcohol ethers of oligoglucosides, fatty acid esters of glycerol, fattyacid esters of polyoxyethylenes, polyethoxylated fatty acid esters ofsorbitan, fatty acid esters of poly(ethylene oxide), fatty alcoholethers of poly(ethylene oxide), alkylphenol ethers of poly(ethyleneoxide), polyoxyethylene-polyoxypropylene block copolymers, ethoxylatedoils, and combinations thereof.
 10. The composition of claim 1, whereinthe phospholipid comprises lecithin, the at least one lipophilicbioactive agent comprises coenzyme Q10, and the permeation enhancercomprises propylene glycol in combination with ethoxydiglycol.
 11. Apharmaceutical composition comprising the composition of claim 1,wherein the pharmaceutically acceptable carrier includes an oil phase,an optional water phase, and an optional neutralization phase.
 12. Thepharmaceutical composition of claim 11, wherein the composition isselected from the group consisting of lotions and creams.
 13. Thepharmaceutical composition of claim 11, wherein the oil phase comprisesemollients, fatty alcohols, emulsifiers, and combinations thereof. 14.The pharmaceutical composition of claim 13, wherein the emollient isselected from the group consisting of C12-15 alkyl benzoates,capric-caprylic triglycerides, vegetable derived oils, caprates,linoleates, dilinoleates, isostearates, fumarates, sebacates, lactates,citrates, stearates, palmitates, synthetic medium chain triglycerides,silicone oils, polymers and combinations thereof; the fatty alcohol isselected from the group consisting of cetyl alcohol, stearyl alcohol,cetearyl alcohol, lauryl alcohol and combinations thereof; and theemulsifier is selected from the group consisting of glyceryl stearate,polyethylene glycol 100 stearate, neutralized fatty acids, partiallyneutralized fatty acids, polyethylene glycol 150 stearate, polyethyleneglycol 8 laurate, polyethylene glycol oleate, polyethylene glycol 8stearate, polyethylene glycol 20 stearate, polyethylene glycol 40stearate, polyethylene glycol 150 distearate, polyethylene glycol 8distearate, and combinations thereof.
 15. The pharmaceutical compositionof claim 11, wherein the optional water phase comprises the permeationenhancer optionally in combination with a viscosity modifier selectedfrom the group consisting of cross linked acrylic acid polymers,pullulan, mannan, scleroglucans, polyvinylpyrrolidone, polyvinylalcohol, guar gum, hydroxypropyl guar gum, xanthan gum, acacia gum,arabia gum, tragacanth, galactan, carob gum, karaya gum, locust beangum, carrageenin, pectin, amylopectin, agar, quince seed, rice starch,corn starch, potato starch, wheat starch, algae extract, dextran,succinoglucan, carboxymethyl starch, methylhydroxypropyl starch, sodiumalginate, alginic acid propylene glycol esters, sodium polyacrylate,polyethylacrylate, polyacrylamide, polyethyleneimine, bentonite,aluminum magnesium silicate, laponite, hectonite, and anhydrous silicicacid.
 16. The pharmaceutical composition of claim 11, wherein theoptional water phase comprises water, glycerine, propylene glycol,ethoxydiglycol, phenoxyethanol, and cross linked acrylic acid polymers.17. The pharmaceutical composition of claim 11, wherein the optionalneutralization phase comprises components selected from the groupconsisting of water, amines, sodium lactate, lactic acid, andcombinations thereof.
 18. The pharmaceutical composition of claim 11,further comprising a pigment.
 19. The pharmaceutical composition ofclaim 18, wherein the oil phase comprises C12-15 alkyl benzoates, cetylalcohol, stearyl alcohol, glyceryl stearate and polyethylene glycolstearate; the water phase comprises glycerine, propylene glycol,ethoxydiglycol, phenoxyethanol, purified water, and a cross linkedacrylic acid polymer dispersion comprising phenoxyethanol, propyleneglycol, water, and a cross linked acrylic acid polymer; theneutralization phase comprised purified water, triethanolamine, sodiumlactate, and lactic acid; and the pigment comprises titanium dioxide.20. A method for treating cancer comprising applying the composition ofclaim 1 to a patient. 21-22. (canceled)